CA125 antigen is a serum marker that is used routinely in gynecologic practice to monitor patients with ovarian cancer. It is a mullerian duct differentiation antigen that is overexpressed in epithelial ovarian cancer cells and secreted into the blood, although its expression is not entirely confined to ovarian cancer. CA125 was first identified by Bast and Knapp (1) in 1981 by a monoclonal antibody (OC125) that had been developed from mice immunized with an ovarian cancer cell line. These investigators subsequently developed a radio-immunoassay for the antigen and showed that serum CA125 levels are elevated in about 80% of patients with epithelial ovarian cancer (EOC)1 but in less than 1% of healthy women (2). Numerous studies since that time have confirmed the usefulness of CA125 levels in monitoring the progress of patients with EOC (3–6). Most reports indicate that a rise in CA125 levels precedes clinical detection by about 3 months. During chemotherapy, changes in serum CA125 levels correlate with the course of the disease. CA125 is being used in the inventors' Medical Center, and elsewhere, as a surrogate marker for clinical response in phase II trials of new drugs. On the other hand, CA125 is not useful in the initial diagnosis of EOC because of its elevation in a number of benign conditions (3, 7). Despite this limitation, CA125 is considered to be one of the best available cancer serum markers, however more information on its molecular nature is needed to fully explore its potential.
Although CA125 antigen was first detected over 20 years ago, very little is known about its biochemistry and genetics. Most biochemical studies have concluded that CA125 is a high molecular weight glycoprotein, although estimates of its size range from 200 to 2000 kDa with smaller “subunits” being described by some investigators (8–13). Most studies have shown that CA125 is a mucin-type molecule, but others have claimed that it is a typical glycoprotein with asparagine-linked sugar chains (14). Another study claimed that CA125 is a glycosyl-phosphoinositol-linked glycoprotein (11). Thus, no consensus emerged from these studies concerning the biochemical nature of this antigen. Recently, however, our studies have strongly indicated that CA125 is a typical mucin molecule with a high carbohydrate content and a preponderance of serine and threonine-linked (O-linked) glycan chains (15, 16). Possibly because of the mucinous nature of CA125 its peptide moiety has been very difficult to clone. The only published study on this topic (17) described the isolation of a novel cDNA, later termed NBR-1 (18), but this species does not seem to have any of the biochemical characteristics expected for CA125 and may, in fact, be a transcription factor. Using a rabbit antiserum to purified CA125 we have now cloned, by expression cloning, a long partial cDNA sequence corresponding to a new mucin species (designated CA125/MUC16A) that is a strong candidate for being the peptide core of the CA125 antigen.